Heterocycl. Commun., Vol. 16(4-6), pp. 217–220, 2010 • Copyright © by Walter de Gruyter • Berlin • New York. DOI 10.1515/HC.2010.016 Preliminary Communication The oxidation of secondary alcohols by dimethyldioxirane: re-examination of kinetic isotope effects A lfons L. Baumstark *, P edro C. Vasquez, Mark 1991 ; Denmark and Wu , 1998 ; Frohn et al. , 1998 ) or in an Cunningham a and Pamela M. Leggett-Robinson b isolated solution (Murray and Jeyaraman , 1985 ; Baumstark and McCloskey , 1987 ). The epoxidation of alkenes and het- Department of Chemistry , Center for Biotech and Drug eroatom oxidation by isolated solutions of 1 in acetone have Design, Georgia State University, Atlanta, Georgia been extensively investigated (Murray and Jeyaraman , 1985 ; 30302-4098 , USA Baumstark and McCloskey , 1987 ; Baumstark and Vasquez , * Corresponding author 1988 ; Winkeljohn et al. , 2004 , 2007 ). Dioxiranes can also e-mail: [email protected] insert oxygen into unactivated CH bonds of alkanes (Murray et al. , 1986 ). However, this important reaction generally requires a dioxirane more reactive than dimethyldioxirane to Abstract be of utility (Kuck et al. , 1994 ; D ’ Accolti et al., 2003 ). The oxidation of secondary alcohols by dimethyldioxirane, 1 , to The kinetic isotope effects for the oxidation of a series of ketones can be achieved in high yield under mild conditions deuterated isopropanols and α -trideuteromethyl benzyl alco- and with convenient reaction times (Kovac and Baumstark , hol by dimethyldioxirane ( 1 ) to the corresponding ketones 1994 ; Cunningham et al. , 1998; Baumstark, 1999 ). Two were determined in dried acetone at 23 ° C. A primary kinetic mechanistic extremes have been proposed for secondary alco- isotope effect (PKIE) of 5.2 for the oxidation of isopropyl- hol oxidation by 1 : a) concerted insertion (Mello et al. , 1991 ; 2-d alcohol by 1 was obtained. The SKIEs for oxidation of Angelis et al. , 2001 ) and b) direct radical-cage processes α -trideuteromethyl benzyl alcohol and isopropyl-1,1,1,3,3,3- (Kovac and Baumstark , 1994 ). Computational model studies d6 alcohol were found to be 1.07 and 0.98, respectively. (Shustov and Rank , 1998 ; Freccero et al. , 2001 ) on dioxirane Oxidation of isopropanol-d by 1 yielded a kOH /kOD value oxyfunctionalization of C-H bonds have been carried out and of 1.12, which is similar to that previously reported for seem to support a stepwise process. Reported kinetic isoto- α -methylbenzyl alcohol-d. Both normal and inverse secondary pic studies have come to differing conclusions concerning the kinetic isotope effect (SKIEs) are observed. Mechanistically, secondary alcohol oxidation process: the initial study (Kovac the results indicate that the process is more complex than the and Baumstark , 1994 ) favored a radical-cage process while a previously proposed models. subsequent study (Angelis et al. , 2001 ) supported a concerted mechanism. We report here a re-examination of the kinetic Keywords: dimethyldioxirane; isotope effects; secondary isotope effects for the oxidation of selected secondary alco- alcohol oxidation. hols by dimethyldioxirane. Introduction Results and discussion Dimethyldioxirane ( 1 ) has been shown to be an extremely The reaction of dimethyldioxirane (1 , in excess) with 2-pro- versatile oxygen-atom transfer reagent for the oxidation of a panol ( 2 ), isopropyl-2-d alcohol ( 3 ), isopropyl-1,1,1,3,3,3-d6 wide range of substrates under mild conditions (for selected alcohol ( 4 ), 2-propanol-d ( 5 ), α -methyl benzyl alcohol (6 ), reviews, see Curci , 1990 ; Adam et al. , 1992 ; Adam and and α -trideuteromethyl benzyl alcohol ( 7 ) (Rxn 1) produced Hadjiarapoglou , 1993 ; Curci et al. , 1995 ; Adam and Zhao , the corresponding ketones in excellent yields. The products 2006 ). In addition, oxidations by 1 can be carried out con- were characterized (where possible) by gas chromatograhy/ veniently either in situ (Corey and Ward , 1986 ; Adam et al. , mass spectrometry (GC/MS) data and by comparison of spec- tra properties with those of authentic samples. The reaction was of the second order overall, fi rst order in both dioxirane and alcohol. Pseudo-fi rst order kinetic studies were carried Present addresses: a1630 Metropolitan Parkway, Atlanta, GA 30310, USA, out in dried acetone with at least a 10-fold excess of the sec- ± ° e-mail: [email protected] ondary alcohol at 23.0 0.3 C employing ultraviolet method- b Georgia Perimeter College – Decatur Campus, Science Department, ology. For all cases excellent pseudo-fi rst order plots were 3251 Panthersville Road, Decatur, GA 30034, USA, obtained (r values were greater than 0.99). Reproducibility e-mail: [email protected] between the kinetics runs of the k2 values was excellent, 218 A.L. Baumstark et al. Table 1 Kinetic isotope effects for the reaction of secondary alcohols 2 – 7 with 1 at 23 ° C in dried acetone. Compound number Structure k2 /M/s Kinetic isotope effect ± × -2 ± 2 CH3 CHOHCH 3 1.62 0.01 10 k H /k D = 5.2 0.1 ± × -2 3 CH3 CDOHCH3 0.31 0.01 10 ± × -2 ± 4 CD3 CHOHCD3 1.67 0.01 10 kCH3 /kCD3 = 0 . 9 8 0.01 ± × -2 ± 5 CH3 CHODCH 3 1.46 0.01 10 kOH /k OD = 1 . 1 2 0.01 ± × -2 ± 6 PhCHOHCH 3 2.17 0.06 10 k CH3 /kCD3 = 1 . 0 7 0.05 ± × -2 7 PhCHOHCD3 2.02 0 . 0 2 10 Table 2 Summary of PKIE data for the oxidation of secondary alcohols by 1 . Entry Alcohol/deuterated alcohol Method (T) kH /k D Reference/Comment ° 1CH3 CHOHCH 3 /CH3 CDOHCH3 Kinetics (23 C) 5.23 Current results ° 2PhCHOHCH3 /PhCDOHCH3 Kinetics (25 C) 3.55 (Kovac and Baumstark , 1994 ) ° 3PhCHOHCD3 /PhCDOHCD3 GC (0 C) 3.6 (Angelis et al. , 2001 ); SKIE effects included ° 4CF3 ArCHOHCH 3 /CF3 ArCDOHCH3 NMR (0 C) 4.8 (Angelis et al. , 2001 ) ° 5PhCH2 OH/PhCD2 OH NMR (0 C) 4.6 (Angelis et al. , 2001 ); SKIE effect included ° 6PhCH2 OH/PhCHDOH NMR (0 C) 4.5 (Angelis et al. , 2001 ); SKIE effect included NMR, nuclear magnetic resonance spectroscopy. generally 1 – 2 % . Second-order rate constants (k2 values) secondary alcohols by dioxirane 1 fall in the range of 3.6 to obtained with a 10-fold excess of dioxirane yielded data con- 4.6. Clearly, all the data are consistent with breaking the sec- sistent with those with excess alcohol but with a larger error ondary C-H of the alcohol in the rate-determining step (rds) range. The primary kinetic isotope effect (PKIE) results for of rxn 1. The current and published PKIE results for second- the oxidation of isopropanol ( 2 / 3 ) was found to be 5.2. The ary alcohol oxidation by 1 are summarized in Table 2. Differentiation between the proposed mechanistic overall secondary kinetic isotope effect for the double CD3 formal substitution ( 2/4 ) was found to be inverse, while that extremes (concerted-direct insertion vs. radical-cage models) is focused on expectations of the secondary kinetic isotope effects (SKIE) for each process. Scheme 1 shows the expected 1 transition states for the extremes. An inverse SKIE would be O O Y OZ expected for the concerted route and a normal value for the k 2 O other. The current and previous SKIE results for the oxidation of secondary alcohols by 1 are summarized in Table 3 . R1 R2 Dried acetone 23ºC In general, the current and published isotope effect data are in good agreement, except for the SKIE effect measured for O α (1) -trideuteromethyl benzyl alcohol oxidation. Entries 4 and 5 appear to be contradictory, but the discrepancy may be due to R1 R2 2 R1=R2=Me, Y=Z=H 3 R1=R2=Me, Y=D, Z=H 4 ‡‡ R1=R2=CD3, Y=Z=H 5 R1=R2=Me, Y=H, Z=D OH . R δ OH 6 R =Ph, R =Me, Y=Z=H R 1 2 H 7 R H R1=Ph, R2=CD3, Y=Z=H R O O O O δ . Me for single CD3 formal substitution ( 6/7 ) was found to be nor- Me mal. The secondary kinetic isotope effect for deuteration of Me Me the alcohol proton on isopropanol ( 2/5 ) was normal: 1.12. The results for compounds 2-7 are summarized in Table 1. Concerted Radical-cage The current PKIE of 5.2 for oxidation of the secondary ali- phatic alcohol 3 to a ketone is in good agreement with those in Scheme 1 Expected transition states for rds for concerted and radi- the literature. The published data for the oxidation of various cal-cage mechanisms of secondary alcohol oxidation by 1 . Secondary alcohol oxidation by dimethyldioxirane 219 Table 3 Summary of ‘secondary’ kinetic isotope effect data for oxidation of secondary alcohols by 1. Entry Alcohol/deuterated alcohol Method (T) Isotope effect ° = ± 1CH3CHOHCH3/CH3CHODCH3 Kinetics (23 C) kOH/kOD 1.12 0.02 ° = ± 2PhCHOHCH3/PhCHODCH3 Kinetics (25 C) kOH/kOD 1.09 0.06 (Kovac, 1994) ° = ± 3CH3CHOCH3/CD3CHOHCD3 Kinetics (23 C) kCH3/kCD3 0.98 0.01 ° = ± 4PhCHOHCH3/PhCHOHCD3 Kinetics (23 C) kCH3/kCD3 1.07 0.04 ° a = ± ± 5PhCHOHCH3/PhCHOHCD3 GC (0 C) kCH3/kCD3 0.98 0.02 to 1.01 0.02 (Angelis et al., 2001) ° a = ± ± 6PhCH2CHOHCH3/PhCD2CHOHCD3 GC (0 C) kH5/kD5 0.98 0.02 to 1.01 0.02 (Angelis et al., 2001) aVia product studies. ‡ deuteration on the R groups would be due to the position- ing of the dioxirane in the transition state. Of course, an H O explanation in which a caged-radical with a strong hydro- O Me gen-bonding component cannot be excluded. Computational O H modeling studies will need to be carried out to evaluate this Me novel process. R R Acknowledgements Scheme 2 Proposed multi-centered transition state for the con- Acknowledgements are made to the US Army ERDEC SEAS subcon- certed oxidation of secondary alcohols by 1 .